Genetic concepts and methodologies serve as the integrating themes for an analysis of several basic phenomena of importance to gerontology. I. A) An already well developed program of research on the in vitro clonal senescence of normal mammalian somatic cells will couple somatic cell genetic investigations with cell kinetic and biochemical analyses to determine the mechanisms limiting the replicative potentials of cultured normal cells and the contrasts in cell cycle regulation between normal cells, cells from patients with Werner syndrome, and neoplastic cells. B) The in vivo clonal senescence of normal hematopoietic cells will also be investigated. II. A newly emerging program of research involving the use of cultured mouse teratocarcinoma cells for the genetic analysis of in vivo aging will be expanded and will include efforts to carry out several types of interspecific gene transfers. III. A newly proposed program of comparative biogerontology, involving Mus musculus, Peromyscus leucopus and Notomys alexis will be coupled with I and II above and will be utilized for tests of the intrinsic mutagenesis and free-radical theories of aging.